Sinnott.

Ann Endocrinol Metab 2018, 2(1):26-33

DOI: 10.36959/433/563 | Volume 2 | Issue 1

Annals of Endocrinology and Metabolism

Review Article Open Access

Pseudohypoparathyroidism-Literature Update 2018

Bridget P Sinnott*
Division of Diabetes, Endocrinology and Metabolism, Medical College of Georgia, Augusta, USA

Abstract
Pseudohypoparathyroidism (PHP) is a rare heterogenous group of disorders characterized by end-organ resistance to
PTH, specifically at the proximal renal tubule. The term PHP encompasses PHP 1A, PHP 1B, PHP 1C, PHP 2 and pseu-
dopseudohypoparathyroidism (PPHP). The two most common subtypes are PHP 1A and PHP 1B, PHP 1A, PHP 1C and
PPHP have the Albrights hereditary osteodystrophy (AHO) phenotype, in addition to end-organ resistance to PTH in
the two former subtypes. Recently, the European Pseudohypoparathyroidism (EuroPHP) network have proposed a novel
classification of PHP which encompasses all disorders of the PTH receptor and its signaling pathway, known as inactivating
PTH/PTH-related protein signaling disorders (iPPSD) [1-6].
PHP is caused by molecular alterations within the GNAS locus. The GNAS gene encodes an alpha subunit of the stimulatory
G protein (Gsα) that mediates the actions of PTH and other hormones including TSH and gonadotropins. It is a defect
in these stimulatory G-protein coupled receptors, that results in end-organ resistance to parathyroid hormone and select
other hormones. Mutations of the GNAS gene are associated with iPPSD2 (PHP 1A, PHP 1C, PPHP, progressive osseous
heteroplasia (POH)) whereas methylation defects are identified at the GNAS locus and associated with iPPSD3 (PHP 1B,
including autosomal dominant-PHP 1B and sporadic-PHP 1B).
This year, the first international consensus statement on the diagnosis and management of pseudohypoparathyroidism was
published and is informative to physicians with limited experience treating these rare disorders. It is important to establish
a diagnosis to enable appropriate medical treatment of the endocrine complications and provide accurate genetic and pre-
natal counselling of individuals and their first-degree relatives.

Keywords
Hormone Resistance, Pseudohypoparathyroidism, Pseudopseudohypoparathyroidism, Albrights Hereditary Osteodystro-
phy, GNAS gene, Chromosome 20q13.3, iPPSD (Inactivating PTH/PTH-Related Protein Signaling Disorders)

Introduction by European Pseudohypoparathyroidism (EuroPHP)

Pseudohypoparathyroidism (PHP) was first described
by Dr. Fuller Albright in 1942 [1]. PHP is an orphan ge-
netic disorder characterized by hypocalcemia, hyper-
phosphatemia, normal vitamin D 25OH, low vitamin D
1,25OH levels and an elevated PTH level, related to PTH
resistance at target organs [2]. The exact prevalence of
PHP is unknown [3]. The estimated prevalence in Den-
mark is 1.1/100,000 [4] and in Japan is 0.34/100,000 [5].
The term PHP encompasses PHP 1A, PHP 1B, PHP
1C, PHP 2 and pseudopseudohypoparathyroidism
(PPHP). The original classification of PHP assigned
sub-types based on the presence or absence of Albrights
hereditary osteodystrophy (AHO), PTH resistance, and
the degree of alpha subunit of the stimulatory G protein
(Gsα) activity using in vitro assays [6,7] (Table 1). An up-
dated classification of PHP disorders has been proposed
network that classifies patients based on their clinical di-
agnosis [8]. The diagnosis of PHP and related disorders
is always initially a clinical diagnosis, which can be fol-
lowed by molecular genetic studies, which confirm the
diagnosis and allow characterization of the subtype [9].
Patients with PHP present with symptoms and signs
of resistance to PTH, occasionally TSH (PHP 1A, PHP1c
*Corresponding author: Bridget P Sinnott, Associate Pro-
fessor of Medicine, Division of Diabetes, Endocrinology and
Metabolism, Medical College of Georgia, 1447 Harper St,
HB-5025, Augusta, GA 30912, USA, Tel: 706-721-2131,
Fax: 706-721-6892
Accepted: September 18, 2018:
Published online: September 20, 2018
Citation: Sinnott BP (2018) Pseudohypoparathyroidism-Lit-
erature Update 2018. Ann Endocrinol Metab 2(1):26-33

Copyright: © 2018 Sinnott BP. This is an open-access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source
are credited.

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 Citation: Sinnott BP (2018) Pseudohypoparathyroidism-Literature Update 2018. Ann Endocrinol Metab 2(1):26-33

Table 1: Classification, Clinical and Molecular features of Pseudohypoparathyroidism [10,18].

Types OMIM Number Hormone Resistance AHO Response to PTH GNAS Abnormality GNAS Defects
[28]
PHP 1A 103580 PTH, TSH, LH, FSH, Yes ↓ cAMP Maternal inactivating Gsα mutations
GHRH ↓ U PO4 mutation
PHP 1B 603233 PTH, TSH No ↓ cAMP Imprinting STX16 or
↓ U PO4 dysregulation NESP55
deletions
affecting GNAS
imprinting
PHP 1C 612462 PTH, TSH, LH, FSH Yes ↓ cAMP Undefined; few Gsα mutations
↓ U PO4 maternal inactivating
mutations
PPHP 612463 None Yes Normal Paternal inactivating Gsα mutations
mutation
PHP 2 203330 PTH and variable multi- No Normal cAMP response, Undefined Undefined
hormone resistance blunted phosphaturic
response
OMIM: Online Mendelian Inheritance of Man; AHO: Albright’s Hereditary Osteodystrophy; PHP: Pseudohypoparathyroidism; Gsα:
Alpha Subunit of The Stimulatory G Protein; LH: Luteinizing Hormone; FSH: Follicle Stimulating Hormone; GHRH: Growth Hor-
mone-Releasing Hormone; cAMP: Cyclic Adenosine Monophosphate; PPHP: Pseudopseudohypoparathyroidism; STX 16: Syn-
taxin 16; NESP 55: Neuroendocrine Secretory Protein 55.

Kidney – PTH leads to: Parathyroid

Bone – PTH leads
↑ Ca reabsorption Glands
to:
↓ PO4 reabsorption ↑ Ca Resorption
Activates 1α-Hydroxylase ↓ iCa ↑ PO4 Resorption
↑ Vit D1,25OH

PTH

PTH Resistance at Small Intestine - ↑ Vit

↑ Vit D1,25OH
Proximal Tubule: D1,25OH leads to:
↓ Vit D1,25OH ↑ Ca absortion
⇒ ↓ Intestinal Ca and ↑ PO4 absortion
PO4 absorption
⇒ ↓ Serum Ca and
↓
serum PO4

Figure 1: Regulation of calcium homeostasis.

and some PHP 1B), follicle stimulating hormone & lu-
teinizing hormone (PHP 1A, PHP 1C) and growth hor-
mone releasing hormone (PHP 1A) [10]. Additionally,
AHO is present in patients with PHP 1A, PHP 1C and
PPHP but is absent in patients with PHP 2. A mild form
of the AHO phenotype can be seen in PHP 1B [3]. PHP
is typically diagnosed in infancy or adolescence but there
are case reports of PHP being diagnosed in adulthood,
particularly PHP 1B and PPHP [11,12].
The genetic defects underlying PHP occurs at the
GNAS locus on chromosome 20q13.2-q13.3, where the
genes encoding Gsα, XLαs and NESP55 lie, as well as
two non-translated transcripts called A/B and GNAS-
AS1 (GNAS complex locus, Antisense Transcript 1) [13].
PTH, along with other select hormones, act through
these G proteins coupled receptors whose signal trans-
duction pathways is mediated by the alpha subunit of the
stimulatory G protein (Gsα).

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 Citation: Sinnott BP (2018) Pseudohypoparathyroidism-Literature Update 2018. Ann Endocrinol Metab 2(1):26-33
Most clinicians have limited experience or expertise
in treating these specialized disorders. Fortunately, the
first international consensus statement on the diagnosis
and management of PHP and related disorders was re-
cently published and will help guide clinicians in treating
this orphan disorder [3].
This paper will focus on the pathophysiology, differ-
ential diagnosis, genetic diagnosis, evolving classifica-
tion, clinical features and management of PHP in 2018.
PTH Pathophysiology
PTH is the predominant hormonal regulator of cal-
cium in the human body and acts primarily at the level
of the kidney, bone and gastrointestinal tract (Figure 1).
PTH is released from the parathyroid glands in the set-
ting of low ionized calcium levels. PTH mobilisers calci-
um from bone, increases intestinal calcium absorption
by activation of 1-α-hydroxylase in the kidney with in-
creased production of activated Vit D 1,25OH and pro-
motes calcium reabsorption in the distal renal tubule.
Additionally, PTH prevents phosphate reabsorption in
the renal tubule, thereby maintaining a normal serum
phosphate level [10].
The hallmark pathophysiologic defect in PHP is renal
PTH resistance; skeletal responsiveness to PTH remains
intact [10]. The defect is located in the proximal renal tu-
bule where 1-α-hydroxylase converts Vit D 25OH to Vit
D 1,25OH. Low Vit D 1,25OH levels lead to hypocalce-
mia, as Vit D 1,25OH is necessary for intestinal calcium
absorption [10]. Additionally, reduced urine phosphate
excretion leads to hyperphosphatemia [10]. Fortunately,
the distal renal tubule remains responsive to PTH and
urine calcium reabsorption is preserved [14], thereby re-
ducing the risk for hypercalciuria or renal stone forma-
tion, which are features of classic hypoparathyroidism.
Skeletal responsiveness to PTH is not affected, therefore
high PTH levels for prolonged periods of time increases
the risk for hyperparathyroid-related bone disease, in-
cluding osteitis fibrosa cystica [15,16].
The PTH receptor (PTHR1) is coupled to the Gsα pro-
tein signal transduction pathway. Normally PTH-medi-
ated activation of this pathway results in an increased
production of serum and urine cyclic adenosine mono-
phosphate (cAMP) [17]. Renal tissue resistance to PTH
at PTHR1 in the proximal tubule manifests as a reduced
urine phosphate and cAMP excretion [17], whereas re-
sistance to PTHrP at the bone could be responsible for
the skeletal abnormalities associated with PHP, both due
to the haploinsufficiency of Gsα coding GNAS gene [3].
Differential Diagnosis
PHP is characterized by hypocalcemia and hyper-
phosphatemia with an elevated PTH level, in the absence
Sinnott. Ann Endocrinol Metab 2018, 2(1):26-33
of vitamin D deficiency or impaired renal function. The
differential diagnosis includes vitamin D deficiency or
resistance, renal failure, hypomagnesemia, acute pancre-
atitis, rhabdomyolysis, tumor lysis, osteoblastic metasta-
sis and hyperventilation [18]. The most common etiol-
ogy that mimics PHP, with low calcium and high PTH
levels, is vitamin D deficiency [19,20]. Hypomagnesemia
is a recognized reversible cause of functional hypopara-
thyroidism and is increasingly seen with the widespread
use of proton pump inhibitors [21]. The differential of
PHP according to phenotype is broad and includes many
endocrine and syndromic disorders, which have been
described in detail in the recent international consensus
paper on PHP [3].
Genetics
A genetic cause can be identified in an estimated 80-
90% of patients with PHP, including both sporadic or au-
tosomal dominant heterozygous inactivating mutations
within the GNAS gene or epigenetic alterations at the
GNAS locus [9], located on chromosome 20q13.2-q13.3
[3]. The imprinted GNAS gene consists of 13 exons that
encode the signaling protein Gsα, a ubiquitous signal-
ing protein mediating the actions of many hormones via
generation of the second messenger cAMP. Even if Gsα
is biallelically expressed in the majority of tissues, ma-
ternal Gsα expression is silenced in tissues with mater-
nal imprinting [22] namely the proximal renal tubules,
thyroid, gonads and pituitary somatotrophs [13,23].
This tissue-specific imprinting leads to a parent of origin
mutation effect: Maternal transmission of the mutations
involves the development of AHO and multi-hormone
resistance (namely, PHP1A and 1C), whereas paternal
transmission is exclusively associated to the phenotyp-
ic features of AHO, without any hormone resistance
(namely, PPHP and progressive osseous heteroplasia
(POH)) [3,24].
PHP1B is caused by loss of imprinting at GNAS lo-
cus, affecting either GNAS A/B: TSS-DMR exclusively or
in combination with any of the other three differentially
methylated regions (DMRs) (GNAS-NESP: TSS-DMR,
GNAS-AS1: TSS-DMR or GNAS-XL: Ex1-DMR) [3,9]. In
most cases of PHP1B these methylation alterations occur
sporadically without any underlying genetic defect, but
some cases are related to heterozygous deletions with-
in STX16 or NESP/AS that imply the loss of methyla-
tion at GNAS A/B: TSS-DMR alone or at the four DMRs
[3,13,23]. Genetic defects at GNAS, observed in patients
with PHP 1A are associated with a generalized deficiency
or reduction in activity of Gsα [7,25], whereas a slightly
diminished activity has been observed in patients with
PHP 1B [26].
Today, the majority of these patients with a clinical
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Table 2: New classification of Pseudohypoparathyroid disorders proposed by the European Pseudohypoparathyroidism Network [8].
Inactivating PTH/PTHrp Signaling Disorders (iPPSD)
New Nomenclature Molecular defects and disease names
iPPSD1 - Inactivating PTHR1 mutations
- Blood strand & Eiken Chondrodysplasia
iPPSD2 - Inactivating Gsα mutations
- PHP 1a, PHP 1c, PPHP/AHO/POH
iPPSD3 - Methylation changes at one or more GNAS DMRs
- PHP1b
iPPSD4 - PRKA1A mutations leading to reduced PKA activity
- Acrodysostosis type 1
iPPSD5 - Activating PDE4D mutations
- Acrodysostosis type 2
iPPSD6 - Activating PDE3A mutations
- Autosomal dominant hypertension with brachydactyly
iPPSDx - Unknown molecular defects
iPPSD n+1 - New molecular defects
PTHrp: Parathyroid Hormone-Related Protein; iPPSD: Inactivating Parathyroid Hormone/Parathyroid Hormone-Related Protein
Signaling Disorder; PHP: Pseudohypoparathyroidism; PPHP: Pseudopseudohypoparathyroidism; AHO: Albrights Hereditary Os-
teodystrophy; POH: Progressive Osseous Heteroplasia; DMRs: Differentially Methylated Regions; PRKAR1A: Protein Kinase
Camp-Dependent Type 1 Regulatory Subunit Alpha; PKA: Protein Kinase A; PDE4D: Phosphodiesterase 4D; PDE3A: Phospho-
diesterase 3A.

diagnosis of PHP are candidate for molecular genet- Table 3: Presentation of Pseudohypoparathyroid disorders by
ic testing. Molecular diagnosis of suspected PHP cas- age in the pediatric population [3,8,49-51].
es must include DNA sequence, methylation and copy Age Presentation
number variant analyses at the GNAS locus [3]. Molecu- Newborn • Congenital hypothyroidism
lar diagnosis of suspected PHP cases must include DNA Infant • Early onset obesity
sequence, methylation and copy number variant analy- • Mild delay in acquisition of milestones
ses at the GNAS locus [3]. • Mild or borderline increased TSH
Toddler < 2 years • Round face
Classification of PHP • Rapid weight gain and obesity
The clinical and molecular overlap among the spec- • Subcutaneous ossifications
trum of PHP and related disorders represents a challenge • Subclinical hypothyroidism
for the clinician. The current classification of PHP is based Children > 2 • Moderate mental retardation
on the presence or absence of the AHO phenotype, spe- years • Brachydactyly
cific biochemical profiles, nephrogenic cAMP response • Afebrile seizures
to exogenous PTH and the in vitro assay measurements • Short stature, subnormal growth rates
of Gsα protein activity [8]. The current classification fails due to growth hormone deficiency
to include related disorders of the PTH/PTHrp signaling • Obesity
pathways such as acrodysostosis, POH and PTH1R-re- • Subcutaneous ossification
lated chondrodysplasia [8]. The EuroPHP network have Adolescence • Pubertal delay due to gonadotropin
proposed an updated classification for PHP, that encom- resistance
passes all disorders with impairments in the PTH and/or • Short stature
PTHrp cAMP mediated pathways, thereby eliminating • Brachydactyly becomes more evident
the clinical or molecular overlap between diseases. This • Dental abnormalities
novel classification is called inactivating PTH/PTH-re-
lated protein signaling disorders (iPPSD) 1-6 [8], (Ta- tween affected individuals, with considerable clinical and
ble 2). This new classification stratifies the disorders into molecular overlap between the different PHP subtypes.
clusters caused by the same mechanism, thereby simpli- Large inter-familial and intra-familial variability has
fying the concept of the overlapping disorders. been observed for the same mutation. There is no cor-
relation between the type or location of the GNAS muta-
Clinical Features tions and the disease onset, degree of hormone resistance
The presentation and severity of PHP vary greatly be- or AHO phenotype [3]. In patients with PHP, resistance

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 Citation: Sinnott BP (2018) Pseudohypoparathyroidism-Literature Update 2018. Ann Endocrinol Metab 2(1):26-33
to hormones namely PTH, TSH, gonadotropins and
GHRH are variably present and attributable to genetic
imprinting [27,28]. The typical presentation of pseudo-
hypoparathyroidism by age, in the pediatric population,
is presented in Table 3. The first international consensus
panel on PHP recommend that the diagnosis of PHP be
based on major criteria, namely resistance to PTH, ec-
topic ossification, brachydactyly/AHO and early onset
(< 2 years) obesity +/- TSH resistance [3]. The diagnosis
of PHP is primarily a clinical diagnosis which should be
followed up with genetic testing to confirm the clinical
diagnosis and allow characterisation of the particular
sub-type.
AHO is a term that describes a number of skeletal and
developmental abnormalities seen in PHP. These include
shortened metacarpals & metatarsals (brachydactyly),
ectopic soft tissue or dermal ossifications, short stature,
round facies and cognitive impairment [10]. The short
stature is attributable to premature closure of growth
plates and short bones [3]. Brachydactyly type E, which
is shortening of III, IV and V metacarpals or metatarsals
and first distal phalanx (wider than long, also known as
potters’ thumb), is a classic finding with the AHO phe-
notype [29] however may not be evident in early life and
may develop overtime [3]. Interestingly, the AHO obesi-
ty phenotype occurs primarily in those individuals who
have multiple hormone resistances and only when the
mutation is on the maternal allele, namely PHP 1A [30].
Patients with PHP typically present with the classic
symptoms of hypocalcemia, related to PTH resistance;
which is seen in 45-80% of cases [3]. This hypocalcemia
related to PTH resistance occurs in the absence of vita-
min D deficiency. The symptoms of hypocalcemia can
range from the asymptomatic, to mild numbness and
paresthesias, to more severe life-threatening signs, with
the development of laryngospasm, tetany and fatal car-
diac arrhythmias [31]. The two hallmark physical exam
findings seen with hypocalcemia are Chovsteks and
Trousseaus signs [31]. Patients may develop a prolonged
QT on electrocardiogram [31]. Symptoms of hypocalce-
mia are not always evident at birth, with normal calcium
and PTH levels however hypocalcemia evolves and un-
masks over their life time [10,32]. Studies in knockout
mice show that the appearance of PTH resistance is de-
layed and develops with age, despite the presence of the
mutation since conception [32].
Hypocalcemia and hypophosphatemia, both of which
are seen in the setting of PTH resistance, can be associat-
ed with the deposition of calcium phosphate products in
extra-skeletal tissues. Calcium phosphate kidney stones,
basal ganglia calcifications, band keratopathy, dental hy-
poplasia and soft tissue calcium-phosphate deposits have
all been described in PHP [3,10,33]. PHP patients are at
Sinnott. Ann Endocrinol Metab 2018, 2(1):26-33
high risk for developing ectopic ossifications at birth or
in early childhood [3], which are a manifestation of Gsα
deficiency in mesenchymal stem cells, with de novo for-
mation of extra-skeletal osteoblasts and the formation
of ectopic bone islands in dermal and subcutaneous fat
[34].
The second most common hormone resistance seen
in PHP is TSH resistance, which manifests as the typi-
cal symptoms and signs of classic hypothyroidism. End
organ resistance to TSH is seen in PHP 1A, PHP 1C and
PHP 1B [3]. Other rare hormone abnormalities include
gonadotropin resistance, Growth hormone deficiency
[35] and hypercalcitoninemia [3,36].
The first large-scale epidemiological study evaluating
morbidity and mortality in a PHP cohort was published
2016. Underbjerg L, et al. [4] reviewed the Danish Na-
tional Patient Registry for patients with PHP and com-
pared them to age and gender matched controls from the
general background population. Compared to the con-
trol population, patients with PHP had an increased risk
of infections (P < 0.01), cataracts (P < 0.01), seizures (P <
0.01) and neuropsychiatric disorders (P < 0.01). Further-
more, the risk of renal disorders, cardiovascular disor-
ders, mortality, malignancy and fractures were compara-
ble with the general background population.
iPPSD2 (PHP 1A and PHP 1C) [8]
Patients with PHP 1A and PHP 1C have features of
AHO and multi-hormone resistance [10]. Patients with
PHP 1A typically has short stature, early onset obesity,
brachydactyly (70-80%), advanced bone age (70-80%),
ectopic ossification (30-60%), as well as neurocognitive
impairment (40-70%) [3]. PTH (100%), TSH (100%),
partial gonadotropin resistance [37] and GHRH hor-
mone resistance can be present with variable severity
and present over a variable time course [6,38-40]. Fe-
males with PHP 1A develop hypogonadism manifested
as delayed or incomplete sexual maturation, oligomen-
orrhea, amenorrhea or infertility [41]. GH deficiency re-
lated to resistance to GHRH has been reported in these
patients [35,42].
Unlike patients with PHP 1A, patients with PHP 1C
have normal Gsα bioactivity in red blood cells [43] but a
blunted cAMP and phosphaturic response. Mutations in
the last exon of GNAS (coding the receptor-interaction
domain) have been detected in a few PHP 1C patients,
suggesting that PHP 1C is an allelic variant of PHP 1A
characterized by Gsα deficiency that selectively affects
receptor coupling functions of Gsα [44].
iPPSD 2 (PPHP)
PPHP was originally described by Dr. Fuller Albright
in 1952 [45]. Patients have the physical features of AHO,
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without the multi-hormonal resistance however some
cases have mild resistance to PTH and TSH [22]. Patients
typically have short stature, normal weight, brachydacty-
ly (< 30%) and ectopic ossification (18-100%) [3].
iPPSD 3 (PHP 1B)
PHP 1B is characterized by renal resistance to PTH, in
the absence of the typical features of AHO. Some patients
may have one or more features of AHO, most commonly
mild brachydactyly (15-33%) [3,46]. These patients typi-
cally achieve average adult height, have early onset obesity
and advanced bone age (15-33%) [3]. TSH resistance can
be seen in 30-100% patients with PHP 1B [3].
Management
The first international consensus statement on the di-
agnosis and management of PHP was published 6/2018
and will assist clinicians managing these rare disorders
[3]. Patients with PHP, with PTH resistance, develop the
clinical manifestations of hypocalcemia and hyperphos-
phatemia, which can be effectively managed with calci-
um supplements and activated vitamin D. Treatment of
PHP should be directed at normalizing serum calcium
and phosphate. The target PTH level is the upper end of
the reference range to minimize the risk for long term
hyperparathyroid related bone disease, [15] hypercalci-
uria and renal calcification [3].
It is recommended that patients have fasting albumin
corrected calcium, serum PO4, Vitamin D 25OH, mag-
nesium, PTH and creatinine values measured at baseline
[47]. Asymptomatic hypocalcemia, may be treated with
oral calcium supplements and if necessary, activated vi-
tamin D, namely calcitriol. Activated vitamin D is pre-
ferred, over ergocalciferol or cholecalciferol, as it doesn’t
require PTH medicated 1-α-hydroxylation in the kidney,
which is impaired in PHP disorders. In the acute setting,
intravenous calcium gluconate and activated Vit D are
necessary to raise the serum calcium [3]. It is necessary
to monitor patient with telemetry during a calcium infu-
sion [47].
Long-term, serum calcium levels are treated to a
higher target than those for classic hypoparathyroidism,
where the treatment target is the low normal range [31].
There are many different formulations of calcium, name-
ly carbonate, citrate and phosphate. These calcium sup-
plements can also function as phosphate binders in the
gut lowering the serum phosphate level. Thiazide diuret-
ics may be necessary to reduce urinary calcium losses,
which are not typically high in PHP, in contrast to classic
hypoparathyroidism [47]. Activated Vitamin D may be
necessary to treat elevated PTH levels that are more than
2 times the upper level of normal, independent of the
presence of hypocalcemia [3].
Sinnott. Ann Endocrinol Metab 2018, 2(1):26-33
Patients with PHP, with PTH resistance, require reg-
ular monitoring of calcium, phosphate, vitamin D and
PTH levels to avoid inadequate or excessive treatment
of their disorder, specifically every 6 months in asymp-
tomatic patients and more frequently when clinically
indicated [3]. Calcium and phosphate homeostasis can
fluctuate during acute illness, growth spurts and during
pregnancy, necessitating more frequent monitoring of
these electrolytes during these time periods [3,47]. Addi-
tionally, patients need to be educated on the symptoms
and signs of both hypocalcemia and hypercalcemia [3].
Other hormone resistances associated with PHP are
generally treated with hormone replacement. The second
most common hormonal resistance is TSH resistance.
This presents with the typical signs and symptoms of hy-
pothyroidism. It is usually limited to patients with PHP
1A, PHP 1C and some patients with PHP 1B. Guidelines
recommend TSH screening every 6 months in patients
< 5years of age and yearly in older children and adults
[3]. It may be necessary to evaluate the gonadotropin
axis (follicle stimulating hormone, luteinizing hormone,
estradiol, or testosterone) in cases of delayed puberty,
infertility or amenorrhea, in PHP 1A and PHP 1C cas-
es [3]. These patients may require exogenous estrogen
or testosterone replacement. Evaluation of the GHRH-
growth hormone axis (growth hormone, insulin-like
growth factor-1) should also be considered in all patients
with suspected PHP IA and PHP IC with poor growth
velocity [3]. Children have been successfully treated with
human GH replacement and have attained a successful
height velocity in the pre-pubertal years [48]. Both chil-
dren and adults with GH deficiency should be consid-
ered for GH replacement therapy [3].
The recent consensus guidelines on PHP recommend
that patients have regular monitoring of BMI, eating be-
haviors, blood pressure, lipids and glucose levels, given
the early onset of obesity (< 2 years of age) [3]. Sleep ap-
nea is another recognized complication of obesity and
patients should be screened with a detailed sleep history
[3].
The current guidelines recommend imaging in pa-
tients with PHP if there is concern for AHO. Plain x-rays
of the hands can easily identify shortened metacarpals.
Chronic hypocalcemia and hyperphosphatemia, related
to untreated PHP, can result in intracranial deposits of
calcium, also known as Fahr syndrome [31]. Basal gan-
glia imaging with a plain skull x-ray or CT head may be
necessary in patients with movement disorders or to ex-
clude other causes of paresthesias or seizures [3]. Patients
may need an ophthalmologic evaluation to evaluate for
cataract development [3]. Patients with PHP are at risk
for bone loss as there is preserved sensitivity to PTH at
the level of the bone, necessitating a need for a bone den-
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sity scan if there are other risk factors for osteoporosis
such as hypogonadism or gonadotropin resistance, GH
deficiency or the postmenopausal status [3].
Management of patients with PHP is complex and
involves life-long management of multi-hormone resis-
tances, metabolic and skeletal complications associated
with this rare disorder. Mutational analysis of the GNAS
gene that identifies PHP 1A, PHP IB and PPHP is avail-
able and may be necessary to definitively diagnose chal-
lenging PHP cases. It is important to make a diagnosis
for PHP and thus treat these patients appropriately to
reduce the severity and complications of the disease.
Conclusions
PHP encompasses a spectrum of orphan disorders
with variable degree of hormone resistance and skeletal
manifestations leading to a limited experience in man-
aging these patients by many clinicians. These patients
need life-long follow-up for metabolic complications,
as well as the development of hormone resistances over
time. The publication of the first international consensus
statement on the diagnosis and management of PHP is
an important contribution to the future management of
these patients. It is important to establish a correct diag-
nosis of PHP to enable appropriate treatment and genet-
ic counselling of these individuals and their first-degree
relatives.
I do not have any conflicts of interest to report.
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